John Podraza, Department of Biological Sciences, Hartwick College,
Oneonta, New York

Abstract

The increasing recreational use of MDMA (methylenedioxymethamphetamine) and
its presumed toxic effects have alarmed many forensic and emergency medical personnel
(Fineschi and Masti, 1996). Numerous cases have been reported in the literature
proposing ecstasy-induced renal damage. A focus will be given to forty-three cases where
ecstasy ingestion has resulted in medical intervention. The nephrotoxic potential of
MDMA in both the animal and the human will be reviewed with a focus on the drugs
mechanism of action.

Introduction

The drug MDMA is classified as an entactogen by Merck (1996) and
chemically resembles a hybrid of amphetamine and mescaline (Hardman et al., 1973).
There are two separate and distinct groups associated with the use of the drug. First is
the medical discipline involved with psychotherapy where MDMA is used as an adjunct to
treat the "physical pain and emotional stress associated with severe medical illness,
post-traumatic stress disorders, depression, phobias, addictions, psychosomatic
disorders and relationship (marital) problems" (Grob and Poland, 1997).

While many researchers have hypothesized to why there is such a
broad difference in observed toxic effects, the primary dispute is one of nomenclature.
The term ecstasy is not automatically interchangeable with MDMA. While medical
research is conducted using pure MDMA, ecstasy tablets sold on the street frequently
contain other substances. The clandestine manufacture of ecstasy often leads to the
intentional, as well as accidental, introduction of contaminants into the tablets (Ziporyn,
1986). An ecstasy tablet can range anywhere from having no hallucinogenic or stimulant
substances what so ever, to being, although rarely so, pure
methylenedioxymethamphetamine. Contaminants include chalk, paracetamol, lysergic
acid (LSD), amphetamines (speed), heroin (smack) (Day, 1996), caffeine, methamphetamine
(ice), methylenedioxyamphetamine (MDA; love), ketamine (special K) (Wolff et al., 1995),
N-methyl-1-(3,4-methylenedioxyphenyl)-2-butanamine (MBDB),
methylenedioxyethamphetamine (MDEA; Eve), 4-bromo-2,5-dimethoxyphenylethylamine
(2C-B; Venus) (Giroud et al., 1998), ephedrine, pseudoephedrine, and triprolidine (Milroy
et al., 1996). Medical clinicians often hypothesize that the reported adverse reactions
associated with ecstasy consumption can be attributable to one or more of these
contaminants.

Various catastrophes have been reported with regards to ecstasy's applied terminology
and interaction with other substances. Tillman et al. (1997) described a case where
several persons ingested what they thought to be MDA, a psychoactive substance similar
in effect to MDMA. Unfortunately this MDA was methylene dianiline p,p-
diaminodiphenylmethane, an hepatotoxic material used in the preparation of polyurethane
foams. Similar misconceptions have been reported with the use of liquid
ecstasy (GHB; gamma-hydroxybutyrate) a highly toxic substance (Thomas et al.,
1997), and herbal ecstasy, an all natural alternative. In 1996 Deb Josefson,
a physician journalist, reported that "fifteen deaths among young people in the US have
been attributable to the herbal stimulant ephedra...marketed as a safe and legal
alternative to street drugs under names such as Herbal Ecstasy..." The recreational use of
ecstasy also has the potential for disastrous effects in patients who fail to disclose
previous drug use on medical history forms. Henry and Hill (1998) noted that ecstasy can
have a fatal interaction with prescription drugs including ritonavir, an HIV medication,
and Nencini et al. (1988) indicated that MDMA can enhance the analgesic properties of
morphine injections.

Numerous other factors can be attributable to the adverse reactions from ecstasy not
seen in the psychotherapy setting. These include high ambient temperatures, aggregation
(crowding), elevated activity levels (dancing/sex), dehydration, and pre-existing medical
conditions. Genetic susceptibility has also been proposed by Tucker et al. (1994). They
conducted a study showing that the debrisoquine hydroxylase enzyme (CYP2D6) in the
liver is responsible for the demethylation of MDMA. Because approximately 5-9% of the
Caucasian population is deficient in the p450 family of enzymes, of which CYP2D6 is a
member, this could lead to an increased toxic risk to those individuals. Several reports
have shown extreme levels of MDMA present in the body without severe complications
(Henry et al., 1992; Ramcharan et al., 1998). This is further evidence for a difference in
metabolism of the drug among individuals. Multiple drug use also poses a problem, but
medical reports showing MDMA present in the blood regularly attribute the negative
outcome to ecstasy. Crifasi and Long (1996) reported the case of a 29 year old male who
operated a motor vehicle inappropriately while under the influence of MDMA. They stated
that unlike other reports, their case was uncomplicated by other drugs. However, later on
in the report Crifasi and Long stated that the operators urine screen tested
positive for amphetamines and cannabinoids.

Therapeutic Use vs. Recreational Use

It is important to make several main distinctions between the
controlled use of MDMA in psychotherapy and the patterns observed in the recreational
use of ecstasy. The preferred psychotherapeutic dose of MDMA is in the 100-150 mg
range with dosing in clinical experiments conducted up to a maximum of 2.5 mg/kg (R.
Doblin, pers. comm.). In 1996 however, McCann et al. reported that "in the setting of
raves, it is not uncommon for an individual to take up to 8 MDMA tablets or capsules
[approximately 800 mg] in one night, once a week." McCann et al. completed another
study in 1998 focusing on 14 exceptionally heavy recreational users and showed that the
average dose and time course of MDMA was 386 mg, 6 times a month. Another important
distinction is the setting in which the use of MDMA takes place. While therapists
administer MDMA in a controlled clinical setting, recreational users taking MDMA at
raves and nightclubs are frequently exposed to hot, poorly ventilated conditions which are
often further compounded by limited water availability and the consumption of alcohol.
The realization of these poor recreational conditions has influenced some event organizers
to provide chill out rooms where MDMA users can go to cool off. Despite these efforts, the
immense differences still prevalent in dose, time course, and setting of recreational
MDMA usage versus that seen in psychotherapy may also be responsible for the observed
toxic effects.

History

MDMA has often been erroneously reported in the literature to have
been synthesized in 1912 as an appetite suppressant by Merck Laboratories, Germany. In
truth, MDMA was an unplanned side reaction that occurred while Merck was trying to
synthesize Hydrastinin, a vasoconstrictor (Gamma, 1998). MDMA was subsequently
patented in 1914 (Merck, 1914), but with the outbreak of World War I received little
investigational attention into the drugs potential applications (Shulgin and
Shulgin, 1991). Grob and Poland (1997) tell of how MDMA came on the scene in the US in
the early 1950s and was tested by the US Army in animals. Alexander Shulgin, a
Berkeley biochemist, is believed to have introduced the drug to the psychotherapeutic
scene after self-administering the drug and testifying to MDMAs rehabilitative
potential (Shulgin and Shulgin, 1991; Shulgin and Nichols, 1978). After several years of
responsible and controlled use by psychiatrists (Greer, 1985; Greer and Tolbert, 1986;
Greer and Strassman, 1985), abuse patterns began to develop by recreational users (Grob
and Poland, 1997). The drug quickly gained in popularity and before long received the
attention of the media and the US Drug Enforcement Agency (DEA). Concerns over the
safety of MDMA grew after Ricaurte et al. (1985) published a report stating that MDA
(methylenedioxyamphet-amine), a precursor to MDMA, damaged serotonin brain cells in
animals. Despite a very controversial and hotly debated battle in court, in 1986 the DEA
classified MDMA as a Schedule I substance, making the drug off limits to both
practitioners and recreational users alike (Young, 1985; Young, 1986; Lawn, 1986).

Since that time, MDMA has grown in popularity as a recreational drug, especially on
the college and rave scenes (Henry et al., 1992; Randall, 1992; Gerada and Ashworth,
1997; Roberts et al., 1997; Nielsen et al., 1995; Schuster et al., 1998; Schwartz and Miller,
1997; Webb et al., 1996; Wright and Pearl, 1995). The National Household Survey on Drug
Abuse (NHSDA), conducted by the Substance Abuse and Mental Health Services
Administration (SAMHSA) in conjunction with the National Institute for Drug Abuse
(NIDA), estimated that in 1995 and 1996 over 6.5 million people in the US age 12 and
higher were lifetime users of ecstasy. In 1997 of the 216 million people represented,
1.5% were lifetime users; the highest percentages coming from the 18 to 25 year old age
bracket.

The controversial use of ecstasy is not a problem limited to the United States, many
other countries have struggled with the same dilemma. In Europe as of 1997, MDMA was
number two on the list of most commonly used illicit drugs (United Nations, 1997).

Since the scheduling of MDMA, many psychotherapists have struggled to regain use of
the drug in therapy. Dr. Charles Grob and Dr. Russell Poland, both of the Harbor-UCLA
Medical Center, have been granted permission to undergo human research into the
psychobiologic effects of MDMA (Dr. Grob, pers. comm.). The FDA has also approved the
psychotherapeutic use of MDMA in cancer patients (R. Doblin, pers. comm.). Dr. Franz
Vollenweider of Switzerland has likewise persevered for the right to study MDMA in his
country (R. Doblin, pers. comm.). Most recently, the Multidisciplinary Association for
Psychedelic Studies (MAPS) has planned a conference in Israel for late August 1999, in
order to facilitate possible MDMA research in the treatment of post-traumatic stress
disorder (PTSD) at Ben-Gurion University of the Negev. Similar research with MDMA in
PTSD treatment has been proposed by Jose Bouso, Ph.D. candidate of the Psychiatric
Hospital of Madrid, Spain, and is currently being reviewed for approval (R. Doblin, pers.
comm.).

Toxicity in Animals

One of the arguments for the scheduling of MDMA was the lack of
toxicology data on the substance (Lawn, 1986). Since then, researchers have scrambled to
evaluate the possible toxicity of MDMA in humans. However, with MDMA being a schedule
I narcotic, obtaining approval for such studies has been rather difficult. While several
important human studies have been conducted, the majority of MDMA research has been in
animals where government approval has been more easily obtained.

Hardman et al. (1973) conducted one of the first toxicology studies of MDMA in the
1950s in order to determine the drugs LD50 (lethal dose) in 5 different mammalian species. Aside from
various behavioral observations, the authors made no reference to MDMAs toxicity
to the kidneys. In 1987, Frith et al. conducted an important and more extensive
toxicological evaluation of MDMA on the dog and the rat, meeting the FDAs pre-
clinical research require-ments necessary before phase 1 and phase 2 human studies
could begin (R. Doblin, pers. comm.). Alterations in blood urea nitrogen (BUN) and
creatinine were observed with varying dose, both indicators of impaired renal function
(see table I). The authors also noted that there was a decreased kidney weight in the male
rats but an increased kidney weight to body weight ratio for both sexes of rat. Frith et al.
further noted a list of histopathologic lesions in the rat including mineralization,
hydronephrosis, calculi, infarct, inflammation, and chronic progressive nephropathy of
the kidneys. However, the authors state, "these lesions are considered to represent
the normal spectrum of spontaneous lesions in rats. No treatment-related microscopic
lesions were evident."

Other studies have shown that MDMA can elevate the core body temperature of the
laboratory rat (Dafters, 1995; Schmidt et al., 1990; Gordon et al., 1991; Nash et al., 1988),
and many suspect that this induced hyperthermia is responsible when altered renal status
is observed. Lalich (1947) showed how dehydration, secondary to hyperthermia, can be a
causal factor in the induced renal failure of animals. Burger and Fuhrman (1964) showed
how animal tissues, including the renal cortex, are susceptible to thermally-induced
damage.

Researchers have struggled to evaluate whether the induced hyperthermia from MDMA
is intensified by various stimuli. Dafters (1995) study indicated that water
consumption and ambient temperature had a direct capacity to enhance or attenuate the
hyperthermic reaction. When MDMA was administered at 11°
C, the hyperthermia was negligible. However, water deprivation in conjunction with an
ambient temperature of 30°
C significantly increased the hyperthermia. In a very interesting study, Malberg and
Seiden (1998) showed that a high ambient temperature has a greater effect on raising the
core body temperature of rats administered MDMA over those receiving saline only.

A study by Gordon and Fogelson (1994) implicated that the cage design for animals in
MDMA studies may be responsible for the hyperthermia observed. The authors report how
MDMA, at 30mg/kg, increased the core body temperature of rats by greater than 2.0°
C when kept in acrylic cages but had no effect in wire-screen cages. Despite these results,
hyperthermia in association with MDMA administration is still a concern for many
clinicians.

One important study by Burns et al. (1996) showed that MDMA administered to rats
activated the renin-angiotensin-aldosterone system. This system is controlled primarily
by the juxtaglomerular cells of the kidney, but the lungs, liver, and adrenal cortex also
play important roles. The implications for this study will be discussed later on, as the
renin-angiotensin-aldosterone system has a consequential position in the etiology of
human toxicity to MDMA.

Toxicity in Humans

Numerous cases have been reported in the literature proclaiming
that ecstasy is toxic to the kidneys. A compilation of renal function indicators (see table
II) was used to review forty-three cases (see table I) where the recreational use of ecstasy
led to some form of medical intervention. A majority of these cases showed several signs
of impaired renal function. The major clinical signs observed included: hyperthermia,
hyperkalemia, hyponatremia, hypo-calcemia, elevated blood urea nitrogen (BUN) and
creatinine (not shown), elevated creatinine kinase, rhabdomyolysis, myoglobinuria,
disseminated intravascular coagulation (DIC), oliguria, acidosis, and acute renal failure
(ARF). Interestingly, all of the previously described signs and symptoms correspond
directly to complications associated with heat stress and exercise (Shrier et al., 1967).
However, hyperthermia was not observed in all cases but this may simply be due to a
prolonged time frame between the onset of illness and the seeking of medical attention. In
1996, Hall et al. stated, "the cases reported in the literature with a full complement
of these features [hyperthermia, rhabdomyolysis, DIC, ARF] mainly have a fatal
outcome." Fortunately, only thirteen of the forty-three cases reviewed here were
fatal, the cause of death frequently being complicated by varying treatment strategies.

Several cases of amphetamine abuse have also been included in table II showing the
close comparisons with ecstasy ingestion. Urinary tract retention (case 1) is a
complication similar in pathogenesis to that of intravenous amphetamine abuse (Bakir and
Dunea, 1996). Rhabdomyolysis is also associated with the use of amphetamines (Scandling
and Spital, 1982; Kendrick et al., 1977) and is diagnosed in the presence of an elevated
creatinine kinase (CK), serum potassium, uric acid, calcium, abnormal serum glutamic-
oxalacetic transaminase (SGOT), and the presence of myoglobinuria (Knochel, 1981;
Koeffler et al., 1976; Grossman et al., 1974).

Histopathology

Unfortunately when the recreational use of ecstasy is associated
with complications like DIC and oliguria secondary to heat stress and exercise,
potentially dangerous procedures such as a biopsy are often contraindicated (Ginsberg et
al., 1970; Schrier et al., 1967). However, a few biopsies/autopsies were performed and
have provided valuable information into the similarities between ecstasy-induced versus
heat stress and/or amphetamine-induced renal tissue damage.

Biopsies were performed in cases 2, 6, and 12 and autopsies were conducted in cases 6,
8, 9, and 11. The results of the biopsies showed a range of histopathological damage to the
kidneys including: extensive tubular degeneration and necrosis, interstitial edema and
hemorrhage, small vessel occlusion, and the infiltration of leukocytes in the renal
medulla. The glomeruli appeared to receive the most damage exhibiting either partial or
complete infarction, loss of epithelial cell foot processes, denudation of the basement
membrane, disarray of cellular organelles, vacuolization of the cytoplasm, and
degeneration of the luminal microvilli. It should be noted however, that atypical changes
in the human glomeruli are frequently observed in the healthy state (Osawa et al., 1966;
Jorgensen, 1966) and often not observed after exposure to thermal stress (Shrier et al.,
1967; Malamud et al., 1946; Vertel and Knochel, 1967; Baxter and Teschan, 1958; Knochel
et al., 1961). The autopsies undertaken showed macroscopically normal kidneys but some
exhibited healed arteritis and the presence of myoglobin in the renal vessels. Several
reports also noted DIC-induced damage to other organs. Thrombi were observed occluding
vessels of the heart and lungs (Bingham et al., 1998; Fineschi and Masti, 1996) and type II
muscle fiber atrophy was noted (Chadwick et al., 1991).

An overwhelming similarity observed in most cases of MDMA-induced
renal failure is the onset of hyperthermia. In amphetamine and methamphetamine abuse,
we know that it is heat injury that plays the causal role in associated renal failure and
coagulopathy (Gary and Saidi, 1979). It has also been shown that heat injury from any
source can cause rhabdomyolysis, coagulopathy, and multiple organ failure (Dar and
McBrien, 1996). Therefore it would seem reasonable to postulate that the hyperthermia
induced by MDMA is responsible for the resultant renal damage especially when one
observes the striking resemblance in the etiology of these cases to that of heatstroke
(Schrier et al., 1967; Malamud et al., 1946; Gore and Isaacson, 1949; Kew et al., 1969; Kew
et al., 1970; Bianchi et al., 1972; Chao et al., 1981; Rubel and Ishak, 1983).

When the MDMA-induced hyperthermia is further compounded by the extreme
environmental factors associated with its use recreationally, a life threatening situation
quickly develops. Cunningham (1997) suggests that ecstasy induces rhabdomyolysis
secondary to hyperpyrexia and possibly extreme oxygen/energy consumption (from
dancing) and crush injury (due to lying unconscious for several hours). Rhabdomyolysis
is a hypercatabolic state where the massive breakdown of muscle is characterized by
muscle pain, weakness, and brown urine. Muscle cells contain a variety of proteins,
enzymes, and electrolytes including: glycogen (for energy), myoglobin (for oxidation),
creatinine kinase, potassium, and phosphate (Saladin, 1998). When a muscle cell is
damaged, sodium, calcium, and water from the extracellular fluid (ECF) enter the cell
while myoglobin, creatinine kinase, and potassium leak out (Davies, 1995). It is this
exchange of enzymes, protein, and electrolytes across the cell membrane that gives rise to
the hyperkalemia, hyponatremia, hypocalcemia, and elevated creatinine kinase levels seen
in cases of MDMA ingestion.

Rhabdomyolysis also causes myoglobinuria. When myoglobin is released from a
muscle cell, it is subsequently picked up by the kidneys and excreted in the urine
turning it brown, hence myoglobinuria. In the healthy state, the human body has a
constant, yet minimal, outflow of myoglobin in the urine. However, when the urinary pH is
less than 5.6, as with metabolic acidosis, the myoglobin protein becomes toxic to the
kidneys by forming a precipitate (myoglobin cast) that consequently occludes the renal
tubules (Davies, 1995). However, as seen in table I, myoglobinuria is very transient and
often not observed even in the presence of rhabdomyolysis (Cadier and Clarke, 1993; Fahal
et al., 1992). Also, myoglobinuria has been associated with exercise in the absence of
substantial heat injury or renal failure (Schrier et al., 1967). Therefore, a presumptive
diagnosis of renal impairment should not be made in the presence of myoglobinuria
alone.

Metabolic acidosis related to ecstasy ingestion may be responsible for various
symptoms cited in the literature and is probably caused by multiple events. Saladin
(1998) describes how acidosis can depress the central nervous system causing confusion,
disorientation, and even coma. The increased number of potassium ions in the ECF
(hyperkalemia), from muscle cell degradation, begins to acidify the blood. Interestingly,
potassium ions can then diffuse into other cells, displacing hydrogen ions, thus lowering
the pH even further. In many cases of ecstasy toxicity, the acidosis is further
compounded when an elevated activity level increases the production of lactic acid. Also,
when dysentery is present, alkaline bases are excreted and the acidosis can quickly
become difficult to control.

Hyperkalemia itself is a dangerous state in the human body and can also be challenging
to manage with ecstasy consumption. Elevated serum potassium levels have the potential
to cause fatal cardiac arrhythmias. Also, if renal tubule necrosis develops, hyperkalemia
becomes even more pronounced as the tubules fail to excrete appropriate levels of
potassium and blood potassium rises further (Cunningham, 1997). This can lead to a
dangerous positive feedback loop as an acidic state can aggrandize the hyperkalemia when
the kidneys preferentially excrete acidic protons over potassium ions.

The combination of hyperpyrexia and the resulting rhabdomyolysis can then lead to
disseminated intravascular coagulation (DIC) (Fineshi and Masti, 1996; Screaton et al.,
1992; Larner, 1992; Henry et al., 1992; Ferrara et al., 1995; Cimbura, 1972; Reed et al.,
1972; Poklis et al., 1979; Lukaszewski, 1979; Nichols et al., 1990; Forrest et al., 1994;
Fahal et al., 1992). A mechanism for the temperature-induced DIC was suggested by
Ginsberg et al (1970) after examining a case of amphetamine intoxication. The authors
noticed that platelet counts did not reach their lowest levels until several days after
thermic insult. Because platelets have a life-span of 3-4 days, this observation suggested
hyperthermically-induced damage to the megakaryocyte, the platelet mother cell. DIC is
diagnosed when a platelet count below 100,000/mm3,
fibrinogen below 40mg/100ml (Ginsberg et al., 1970), and a prothrombin time less than
12.5 sec. is observed (see table I). DIC can lead to microvascular obstruction as fibrin-
platelet complexes form on the inside walls of blood vessels. This obstruction could
potentially effect any organ including the kidney, in which case it would cause ischemia
and eventually necrosis (Fahal et al., 1992). It may also cause a lesion similar to that
seen in thrombotic thrombocytopenic purpura (Eknoyan and Riggs, 1986).

Hyperthermia also has the potential to induce a state of dehydration especially when
combined with elevated activity levels, inefficient fluid replacement, and the consumption
of alcohol. A low blood pressure and high blood osmolarity subsequently develop and in
conjunction with hyponatremia activates the renin-angiotensin mechanism (Saladin,
1998). The main focus of this mechanism is to stabilize glomerular filtration rate
allowing for a steady excretion of toxic nitrogenous wastes from the body. Interestingly,
the use of MDMA has been shown in rats to further enhance the activation of this system
(Burns et al., 1996). In the renin-angiotensin mechanism, the JG cells of the kidney
release the enzyme renin and through a series of metabolic steps, the hormone angiotensin
II is produced. Angiotensin II then stimulates vasoconstriction which restricts renal
blood flow. In the healthy state this restriction should not effect waste excretion.
Although in the case of MDMA, elevated serum levels of urea nitrogen and creatinine are
observed suggesting impaired glomerular blood flow possibly due to coagulopathy.
Angiotensin II also produces an increased re-absorption of water which can lead to an
oliguric state (urine output of less then 500ml/day). Prolonged oliguria is an additional
cause of azotemia, the buildup of toxic nitrogenous wastes in the blood, and may also be
the result of necrotizing glomerulonephritis, renal vascular breakdown, or excretory
obstruction (Loughridge et al., 1960). Furthermore, Angiotensin II, in conjunction with
hyperkalemia and hyponatremia, stimulates the adrenal cortex to secrete aldosterone.
Aldosterone consequently enhances the re-absorption of sodium (and therefore water) and
excretion of potassium at the distal convoluted tubule and collecting duct of the kidney
thus elevating blood pressure.

Angiotensin II also creates a feeling of thirst in an attempt to stimulate the body
towards re-hydration. However, due to the psychoactivity of MDMA, this feeling may be
dangerously enhanced or attenuated. When excessive water intake is observed, a severe
acute hyponatremic state frequently develops (Bingham et al., 1998; Maxwell et al., 1993;
Satchell and Connaughton, 1994; Williams and Unwin, 1997; Matthai et al., 1996). Sjoblom
et al. (1997) argue that water intoxication should not cause hyponatremia unless renal
function is impaired or an increase in anti-diuretic hormone (ADH) secretion is observed.
In 1998, Henry et al. conducted a study in humans showing that a single dose of 47.5mg of
MDMA did in fact increase the baseline arginine vasopressin (AVP; ADH) concentration
which saw a consequent reduction in sodium concentration. In 1993, Maxwell et al.
diagnosed a woman with syndrome of inappropriate anti-diuretic hormone secretion
(SIADH) after MDMA consumption but were beleaguered by the fact that she drank five
liters of water, developed dilutional hyponatremia, but then did not respond by diuresis.
This appears rational as MDMA has been shown to cause massive releases of serotonin in
the brain and we know ADH secretion is regulated by serotonin (Iovino and Steardo, 1985).
The protocol for the diagnosis of SIADH is an elevated urine osmolality and sodium
excretion with a low blood osmalility and sodium content (Satchell and Connaughton,
1994).

The Serotonin Syndrome

A number of articles reporting on the adverse reactions associated
with the use of ecstasy in the recreational setting have implicated the serotonin syndrome.
Sternbach (1991) and Bodner et al. (1995) tell us that the syndrome is diagnosed when a
known central serotonergic agent is administered resulting in at least three of the
following complications: "mental status or behavioral change (confusion, agitation,
hypomania, coma), alteration in muscle tone or neuromuscular activity (incoordination,
shivering, tremor, hyperreflexia, myoclonus, rigidity), autonomic instability
(diaphoresis, tachycardia, hypertension, hypotension), hyperpyrexia, and diarrhea."
They also state that when the serotonin syndrome can be diagnosed in the presence of
elevated temperature possible complications include DIC, rhabdomyolysis, cardiac
dysrhythmias, renal failure, seizures, coma, and death. The syndrome has been
specifically diagnosed in several cases reported here (Dar and McBrien, 1996; Green et al.,
1995; Huether et al., 1997), and appears to be an accurate deduction considering that
MDMA is a known central serotonergic agent.

Conclusion

After careful and critical evaluation of all available data, and in the
absence of a definitive study focusing specifically on the kidneys, one can only deduce
that MDMA is not a direct nephrotoxin. While the drug does play a causal
role, MDMA does not play the causal role in nephropathy. In fact, when
impaired renal function is observed after the ingestion of ecstasy, multiple factors are to
blame. The only true causal role that MDMA plays is to induce a hyperpyrexic state. If
the developing hyperthermia is further compounded by predisposing conditions (Hall,
1997), high ambient temperatures, crowding (aggregation), loud noise, alcohol/multi-drug
use, inefficient fluid replacement, and elevated activity levels only then might the
kidneys respond via ineffective functioning. Of course, these conditions only increase the
possibility for impaired renal performance and may in fact lead to other complications or
even no adverse reaction what-so-ever (Logan et al., 1993). We must also remind ourselves
however, that genetic susceptibility and the ever abounding impurities in the street drug
may increase the observed toxicity although MDMA is not to blame.

Research In Progress

A study is currently in progress by the author focusing closely on the
effects of MDMA administration and its influence on kidney function in the rat. MDMA is
being administered at 2.5 & 5.0 mg/kg p.o. once weekly for 7 weeks in an
environmentally controlled atmosphere. The main purpose of the study is to examine
whether changes in renal clearance, renal vasculature, and renal tissue integrity are
observed with MDMA administration in the absence of the environmental factors
frequently associated with the adverse reactions seen recreationally in humans.

Acknowledgments: This work was funded by a research grant from the
Multidisciplinary Association for Psychedelic Studies, Inc. Special thanks is given to Mr.
Rick Doblin for his expert critique on this manuscript. Appreciation is also given to Dr.
Allen Crooker for his inspiration, and Prof. Mary Whitlock & Ms. Alison Whitlock for
their administrative assistance.

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